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Motility of the terminal ileum and ileocecal sphincter in healthy humans
GASTROENTEROLOGY
1984;87:857-66
Motility of the Terminal Ileum and Ileocecal Sphincter in Healthy Humans E. M. M. QUIGLEY, T. J. BORODY, M. WIENBECK, R. L. TUCKER, and Gastroenterology
Unit, Mayo Clinic,
Rochester,
Factors controlling the transit of contents between the ileum and cecum should be important determinants of intestinal function; however, the dynamics of the ileocecal region remain largely unexplored in healthy humans. Accordingly, prolonged recordings of intraluminal pressure were obtained from the distal ileum, across the ileocecal sphincter, and from the proximal colon of healthy adults. In one set of studies, 16 subjects each contributed 6 h of basal, fasting recordings; in 2 of the 16, postprandial patterns were also recorded. In a second set, 6 fasting subjects were studied for a total of 120 h. Less than 10% of interdigestive cycles (migrating motor complexes) reached the ileocecal sphincter. The remainder faded out and merged into an active, apparently random pattern of pressure waves that became more intense closer to the sphincter. Discrete, short bursts of phasic pressures migrated rapidly for long distances in the distal ileum and a unique peristaltic wave also migrated rapidly, though infrequently, through the region. Tonic pressures were recorded across the ileocecal sphincter but were present only during the passage of phasic
Received January 27, 1984. Accepted April 17, 1984. Address requests for reprints to: Sidney F. Phillips, M.D., Gastroenterology Unit, Mayo Clinic, Rochester, Minnesota 55905. E. M. M. Quigley’s present address is University Department of Medicine, Hope Hospital, Eccles Old Road, Salford M6 8HD, United Kingdom. This study was supported in part by Grants RR00585 and AM32121 from the National Institutes of Health, Bethesda, Maryland. Dr. Quigley was an International Research Fellow of the Fogarty Foundation (TWO 3117). Dr. Borody was supported by a Neil Hamilton Fairley Fellowship from the National Health and Medical Research Council (Australia). Dr. Wienbeck was supported by a grant from the Minister fuer Wissenschaft und Forschung in Nordrhein-Westfalen (Federal Republic of Germany). The authors thank the nurses of the General Clinical Research Center, Mayo Foundation for their help with these studies and Mrs. Deborah Frank for expert secretarial assistance. 0 1984 by the American Gastroenterological Association 0016-5085/84/$3.00
S. F. PHILLIPS, A. HADDAD
Minnesota
pressure waves; basal tone was minimal. We believe these are the first prolonged observations of motility from the ileocecal sphincter of healthy humans. These descriptions provide insights into and a basis for further studies of a largely unexplored area of the human bowel. The junction between the ileum and colon is the least explored site of the gastrointestinal tract, and yet it probably represents an important transition zone. Some functions of the ileum are quite specialized, active absorption of bile acids (I) and of vitamin B12 (2) being the most obvious examples. In addition, the ileocecal junction separates the abundant and complex flora of the large bowel from the less contaminated ileum (3), and the consequences of bacterial overgrowth in the small bowel are well recognized (4). Thus, the large and small bowels are compartmentalized by the ileocecal junction which in the dog (5) and humans (6) exhibits a segment of “tonic” pressure; the zone relaxes with distention of the ileum and contracts with distention of the proximal colon. These characteristic properties of a “sphincter” are supported further by the unique cellular properties of muscle from the junctional zone (7) of the cat, including specific responses to pharmacologic agents (8,9). A second possible function of the ileocecal junction is any influence it may have on the transit of thyme from ileum to colon. The human colon absorbs up to 1500 ml of thyme daily (lo), a value that can be increased threefold to fourfold under appropriate conditions of loading (11). The rapid infusion of fluid into the cecum (ll), however, impairs transiently the capacity of the colon to compensate. Thus, transit of fluid from ileum to colon, as influenced by patterns of motility, has the potential of influencing the colon’s ability to respond to increased loads. Abbreviations MMC. migrating
used in this paper: motor complex.
ICS,
ileocecal
sphincter:
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We have established that the canine ileocolonic junction has a motor pattern that varies cyclically during fasting (12,13),with cycles of interdigestive motor activity passing through the terminal ileum as far as the ileocolonic sphincter (12). Thus, an understanding of the dynamic functions of this region requires prolonged observations that can appreciate cycles of activity that have a periodicity of l-2 h. Furthermore, the canine ileum can propel contents fashion (13,14). Prominent high in a “peristaltic” pressure contractions, which are propagated rapidly, constitute an effective mechanism for emptying loops of canine ileum (14). Further exploration of this region in intact humans seemed worthwhile, as reports of its functional characteristics are confined currently to the simplest of observations (15,16). The present study was designed to evaluate, by measurements of intraluminal pressure, the motor patterns of the terminal ileum, ileocecal sphincter (ICS), and cecum in intact humans. It was our intent to extend our earlier observations in the dog (12-14) as well as those on motility and flow in the terminal ileum of humans (17-20).
Material and Methods
Vol.
87.
No. 4
included also one or two radiopaque tubes (Ferraris Engineering, Edmonton N18. London. England), one of which ran the length of the assembly. This facilitated localization of the tube fluoroscopically and also served to inflate with air a balloon that surrounded the terminal mercury weight. Inflation of the balloon speeded passage of the assembly through the bowel (23). The balloon was deflated when the assembly reached the cecum. Location of the tube was by and end of each fluoroscopy (Figure 1) at the beginning study, and by visual inspection of tracings during the recording sessions. Thus, the characteristic frequencies of phasic pressure waves in the ileum and colon could be
recognized [Figure 2). Recording lumens were perfused with water by a low compliance system (24), the details and validation of which have been reported previously (17). Pressures from the perfused catheters were recorded. via transducers (Statham-Gould, P-23, Statham Instruments, Inc., Halto Rey, Puerto Rico), by two synchronized multichannel recorders (MFE 1600). The technique was acceptably comfortable for most volunteers; 26 individuals were intubated for a total of 22 successful experiments. In the first 16 subjects (group A), intraluminal pressures were measured from the terminal 30-50 cm of ileum, across the ICS, and from the proximal colon. The sensors were located (in centimeters from the aborad end of the tube) at 0, 5, 6.5, 8.0, 9.5, 11.0, 12.5. 17.5, 22.5, 37.5, and 52.5 cm. Thus, when the terminal sensor was in the proximal colon, the closely spaced array of sensors straddled the ileocecal junction (Figure 1). It was not possible to
Two sets of studies on healthy, adult volunteers are reported. None had symptoms or a past history of significant gastrointestinal disease and all gave written informed consent for the protocols that were approved by the Mayo Clinic’s Human Studies and Radiation Control Committees. The first group of 16 subjects (11 men, 5 women; aged 20-71 yr) participated in a 24-h study that included observations of the effects of drugs on ileocecal motility, the details of which will not be included here. These have been described in abstract form elsewhere (21,22). However, as part of the study, a 6-h recording of basal, fasting motility (before the administration of any drugs) was available from each subject. It is these recordings that form the basis of the present results. Two of the 16 subjects received placebo drugs throughout the 24-h study and were also given a mixed meal of 600 kcal (40: 40: 20; fat/carbohydrate/protein); 12 h of postprandial recording were available in these subjects. A second group of 6 subjects (4 men, 2 women; aged 20-47 yr) were studied with a different recording system for 18-22 h fasting, and without the administration of drugs.
IntraJuminaJ
Sensors
and
Study
Design
Intraluminal pressures were recorded from opentips cut into an array of polyvinyl tubes (Dural Plastics, Dural 2158, New South Wales, Australia). Each component tube had an external diameter of 2.0 mm and featured three individual lumens, of internal diameter 0.78 mm. The composite assembly, of three triple-lumen tubes, was prepared locally by gluing the components together. We
Figure
1. Radiograph of tube assembly in position. Sites open-tip sensors are indicated by small metal The closely spaced sensors straddle the ileocecal tion.
of the plugs. junc-
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MOTILITY OF ILEOCECAL REGION
1984
TERMINAL ILEUM (30 cm from ICS)
9.25 min-’ ILEOCECAL SPHINCTER
6 min-’ Figure 2. Compendium recording from 1 subject showing phasic waves at the maximum rate for each locus: i.e.. the frequency of the corresponding slow wave (BER or ECA). The ileal frequency, 8-10 min- I, can be distinguished from that at the ileocecal sphincter (ICS). 7-8 min ‘, and the cecum. 6-7 min ‘. The time bars are of 2 min.
obtain exactly the same tube position in all subjects. However, by fluoroscopy, before and after the study, and by visual counting of contractile frequencies (Figure 2). the position of the ileocecal junction could be localized to within l-3 cm of tubing. We report here a total of 98 h of fasting recording from these 16 subjects. In the second set of six studies (group B), the locations of the side-hole sensors were different. They were at 0, 10, 20, 30,40, 50, 75, 100, and 125 cm from the aborad end of the tube. The assembly was passed 10-30 cm into the colon. so that the more proximal sensors spanned -100 cm of ileum. A total of 120 h of fasting recording was accumulated from 6 subjects. Our aim here was to examine fasting patterns of motility over the distal 100 cm of small bowel, whereas in the first set of experiments, the sensors were located within the terminal 40-50 cm of ileum, with the ICS receiving particular attention.
Motility Patterns-Definitions Statistical Evaluation
and
Records were analyzed visually, by at least two observers who agreed as to the presence of the various motor patterns. For phase III of the migrating motor complex (MMC) to be defined required the presence of 3 min of uninterrupted, phasic pressures at the maximum frequency (7-llimin) for that locus of the small bowel (17). Phasic contractions in the proximal colon were slower (maximum Gimin) than in the ileum. To be catego-
rized as progressive, phase III needed to be recorded sequentially in three adjacent channels or from the two most proximal channels. When rhythmic bursts of phasic contractions of shorter duration (~3 min) were recorded, they were designated as “discrete clustered contractions.” These were most prominent in the upper ileum, some being propagated between adjacent sites, but others could
IN
HlJMANS
859
easily be seen to propagate. For the recognition of patterns and for the counting of total contractile events, pressure waves under 8 mmHg in amplitude were ignored
not
because it was difficult at times to distinguish these lesser amplitudes from respiratory excursions. Single pressure waves, which had a duration longer than the ileal slow wave (6-8 s), often lasting more than 30 s, and sometimes achieving pressures in excess of 100 mmHg, were seen to propagate rapidly through the distal ileum. These were designated as “prolonged propagated contractions.” Tonic pressures at the ICS were measured from the “trough” of phasic contractions to baseline pressure. in the sensor judged to be closest to the sphincter segment. For comparisons, the same measurements were made on simultaneous recordings from an ileal sensor located away from the KS. Where appropriate, statistical comparisons were made by paired or unpaired t-tests.
Results Positioning
of Tubes
Assemblies passed into place usually in 6-8 h. The mean length of tubing needed to reach the cecum was 208 cm (178-240 cm) beyond the teeth. Subjects tolerated the study well, sleeping during the overnight phase. Tubes were well maintained in place after deflation of the terminal balloon, a few centimeters of progression further into the colon being sometimes noted at the final fluoroscopy. In 4 subjects, the assembly did not cross the ileocecal junction or inspection of recordings suggested advancement of the tube far into the colon; interim fluoroscopy and retrieval of tubing was then required. These studies were discarded. A few subjects noted mild nausea or discomfort within the throat, but no other side effects were reported or observed.
Overall
Patterns
of Motility
Much of the time, recordings displayed an apparently random pattern of ileal contractions (Figure 3), similar to that reported for phase II at other loci in the small bowel (17). This pattern of random contractions became more intense (i.e., showed more contractile activity per unit time) close to the ileocecal junction. Superimposed upon these random contractions were the more organized patterns, phase III of the MMC (Figures 3 and 4) and discrete clustered bursts [Figures 3 and 5), as well as prolonged propagated contractions (Figure 6). A gradient in the prevalence of random contractile activity along the terminal ileum was quantified in group B. All contractile events were counted at different loci for one interdigestive cycle in each subject (excluding phase III). The number of contractions increased twofold to fivefold between the most
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QUIGLEY ET AL.
GASTROENTEROLOGY
Vol. 87, No. 4
orad sidehole (-100 cm proximal to the ICS) and the side hole closest to the junction (Figure 7). Migrating Motor Complexes Phase III of the interdigestive cycle (MMC) was recognized in the terminal ileum and occasionally was seen to involve the ICS and cecum. Figure 4 shows clearly a burst of phase III activity passing through the terminal ileum, across the ICS, and into the cecum. Such progression, however, was unusual. More often, phase III activity fronts became attenuated toward the ICS; they were less well defined, and not so well demarcated by a subsequent period of phase I quiescence (Figure 3). Thus, in 98 h of recording from the 16 studies in group A, only three typical phase III patterns were identified. It was this finding that prompted the design of the group B studies in which phase III activity was sought over a longer segment of ileum. In 120 h of recording from the second group of studies, the attenuation of phase III activity toward the ICS could be quantified (Table 1).Only one-third of the phase III activity fronts identified in the proximal sensor reached a point 40 cm from the ICS and only 2% reached the ICS. Other “MMC-like” patterns were seen in the ileum but these appeared to originate these for they could not be linked to “fronts” passing into the upper ileum from above. Table 1 also demonstrates that the MMC slows and lengthens toward the ICS. Discrete Clustered
Contractions
This pattern encompassed bursts of phasic contractions at the rate of slow waves for each level of the small bowel. Their durations were shorter than those of the MCCs; they lasted 20-80 s (mean 44 s). These grouped waves were variably present among individuals (Table 2).In some tracings, they were very prominent (Figure 5) and when well developed, they appeared rhythmic with a periodicity between 31 and 46/h (mean 36/h). It was often not possible to define the propagation of these patterns precisely. In some instances, propagation over three sequential recording sites was clear (Figure 5), but on other occasions the presence of intense random contractions may have obscured any propagation. In the most obvious examples, propagation was rapid, 30-250 cm/min (mean -120 cm/min) and over distances in excess of 50 cm. Prolonged
Propagated
Contractions
These striking
waves were of long duration amplitude (50variability was again noted; some persons having none during 6 h of (12-40 s) and often of considerable 100 mmHg) (Figure 6). Individual
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1984
MOTILITY
OF ILEOCECAL
REGION
IN HUMANS
861
Terminal Ileum
ICS Colon
Figure
4. Recording of intraluminal pressures from the human ileum, ileocecal progression of phase III down to, and through. the ileocecal sphincter: terminal ileum (compare with Figure 3).
recording and 1 person having up to 3 per hour. These waves propagated rapidly (20-120 cm/min, mean -60 cmimin), were seen predominantly in the distal 20-30 cm of ileum, and some crossed the ICS. Figure 6 (right panel) shows also that phasic activity may follow the prominent, single wave. Tonic Pressures
at the Ileocecal
sphincter (ICS). and cecum. This example this was an unusual event, phase III usually
shows clear faded in the
was present for the majority of recording time and tonic elevation of the baseline was present only during times of sustained phasic contractions at the
Sphincter
Tone was present only intermittently at the ICS. When records from the sensor(s) judged to be closest to the ICS were examined, no tonic pressure
Distance from ICS
35 cm A--. \ \
25 cm * 15 cm W
Figure
11
--
.. .s
5. Recording of intraluminal pressure from ileum, ileocecal sphincter (ICS), and cecum of a healthy record are groups of phasic contractions (“discrete clustered contractions”) that appear at a frequency min. ‘The dotted lines are arbitrarily drawn and represent only one possible pattern of propagation.
adult. Prominent in this of about one burst per 2
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GASTROENTEROLOGY
5OmmHg b mln
cm Figure
6. Recording of intraluminal pressure from ileum, ileocecal sphincter (ICS). and cecum of a healthy adult. Prominent phasic contractions that last 20-40 s, and that are propagated rapidly down to the ileocecal sphincter (‘*prolonged contractions”]. Though usually single, some examples are followed by (right panel) repetitive, phasic waves.
Postprandial
Patterns
Twelve hours of recording are reported from 2 subjects in group A who received only placebo drugs. The usual pattern of intense random contractions (“fed pattern”) was seen. No MMCs, discrete
\ t \\ \ f
01
’
I
I
125
90
55 -Ileum
I
I
I
I
I
I
40 30 20 10 0 -10 Teninal ileum ICS Colon
Position of sensor Figure
Vol. 87. No. 4
(CM proZel.sICS)
7. Total number of contractions at various loci of the distal ileum. The numbers of single contractile events were those occurring after the end of one phase III burst (migrating motor complex, MMC) up to the beginning of the next. When MMCs were not present in those recordings from close to the ileocecal sphincter (ICS), an equivalent recording time to that evaluated proximally was used. The total number of pressure waves increases severalfold up to the ICS. (n = 6 subjects, vertical bars = SEM.)
clusters, or prolonged identified.
propagated
are single, propagated
contractions
were
Discussion Certain functions of the ileocecal region in humans were observed grossly and reported early in the century (15,16,25). When seen through intestinal stomas, a consistent feature was that thyme was expelled intermittently and forcefully from the ileum. These findings suggested that ileocecal motility was coordinated and that the terminal ileum could develop powerful propulsive (“peristaltic”) forces. These early observers also noted that ileal peristalsis “frequently fails to reach the sphincter” (16)and occurs once or twice per hour (15,16,25); in addition, radiopaque food was often stored in the ileum (25). The possibility is raised, therefore, of incomplete emptying and storage of content by the ileum. The human ileocecal sphincter was first studied quantitatively by Cohen and his colleagues (6,26). They took the opportunity offered by patients who had their colons defunctioned surgically for the treatment of portosystemic encephalo,pathy. They performed “pull-throughs” across the sphincter, and confirmed the findings of Kelley and DeWeese (5) in the dog. A mean tonic pressure of 20 cmH,O could be recorded over a distance of 4 cm; basal pressures were augmented by cecal distention and reduced by ileal distention (6). They also evaluated the influ-
October
Table
MOTILITY
1984
1. Occurrence
of Phase
III Contractions
(Migrating
OF ILEOCECAL REGION IN HUMANS
a63
in Human Ileum and Its Relationship to
Motor Complexes)
Ileocecal Topography Phase Approximate location of sensor”
Sensor No.
Total No.
115 90 65 40 30 20 10 ICS Colon ICS, ileocecal
sphincter:
motor
9.3 10.0 13.7 17.2 la.3 20.2 17.2 18.8
complex.
of gastrin on the sphincter (26); exogenous gastrin or alkalinization of the antrum reduced sphincteric tone. After these reports, the region remained largely unexplored in humans until it became possible to record accurately intraileal pressures (171, using fine, multilumen flexible catheters, and using sensitive, reliable low compliance systems (24). The present studies were further facilitated by tube assemblies that enabled the ileocolonic region to be intubated rapidly and reproducibly (23). Using these approaches, it was possible for the first time to observe patterns of motility in the healthy terminal ileum, ICS, and cecum. Our first important finding was that it was distinctly unusual for the MMC (phase III of the interdigestive, myoelectric complex, “activity front”) in humans to traverse the entire terminal ileum, through to the ICS. Though we recorded examples of an MMC progressing into the colon (Figure 4), these were the exceptions. More often, phase III sequences became unrecognizable within the apparently random activity that predominated in the distal ileum. The electrical equivalent of the MMC, as first described in dogs, traversed the entire small bowel (27) and, in other species, MMCs are assumed to progress to the ileocecal junction (28). However, the pig’s
2. Characteristics
of Discrete
Duration of record Subject 1
19
22 15 22 23 21
a Range
Total No.
(hl
2 3 4 5 6 20-80
s. ” Range
Clustered
417 3 a9 a5 175 294 30-250
cmimin.
’Obvious
Contractions
proximal
to ileocecal
k -+ + t -c f 2 2
Maximum phasic rate” (min I)
0.6 0.2 0.4 0.5 0.9 1.6 0.2 0.2
11.9 t 0.3 10.9 t 0.3
10.4 9.8 9.6 a.8 8.6 8.0 6.9
sphincter.
” Mean
-+ + + -t + t +
0.3 0.2 0.3 0.3 0.4 0.6 0.3
k SEM
small bowel is similar to that of humans; in one report (29), 35% of MMCs were not conducted over the entire small bowel, but “disappeared” in the ileum. Our figure for attenuated MMCs is larger in humans (?90%), recalling the earlier report of “peristalsis” often failing to reach the sphincter in 1 patient (16). Previously, we (17) have described ileal MMCs as occurring with the same cycle length as those of the proximal small bowel; in other words, Kerlin and Phillips (17) did not note that phase III disappeared in the terminal ileum. The results of experiments in series A, in which phase III was an infrequent event (3 MMCs in 98 h), were in sharp contrast to our earlier findings (17) of 18 MMCs in 37 h of recording. This surprising disparity was the rationale for the experiments of group B. Thus, in the study by Kerlin and Phillips (171, the most distal sensors were usually 20-30 cm orad to the ileocecal junction, whereas in the group A studies, the most proximal sensors were 40-50 cm orad to the ICS. The experiments .of group B, which traced MMCs over a loo-cm segment of terminal ileum, showed clearly that many human MMCs, like those of the pig, disappear in the terminal ileum (Figure 8). Differences among species are highlighted further by our own results in the dog: although ileocolonic
in Human
Mean duration”
Ileum
No. showing clear propagation
Lsl 41 42 46 43 47 46 progression
3.1 1.5 1.2 1.0 1.6 1.4 0.6 0.7
f 1.7 f 2.2 2 2.0 -’ 4.0 t 4.5 -c 4.2 2 7.8 + 12.0 16.2
” In centimeters
ence
Table
Velocity between adjacent sensors”(cm/min)
Duration” (min)
a5 60 48 29 12 a 4 3 2
MMC. migrating
III (MMCs)
128
9 24 35 not noted
in these
subjects.
Velocity” (cm/min]
Minimal distance traversed (cm]
1 o-1
56
125 101 46
63 65 57
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QLJIGLEY ET AL.
GASTROENTEROLOGY
n=16 6’6 h
recording
122 h recording
B
120
90
Distance
60
from ICS - cm
40
30
20
10
TR'emu';6i
0 IES
-10 Colon
Figure 8. Topographic distribution of the occurrence of MMCs at different levels of the ileum, ileocecal junction, and cecum. Panel A shows results from 16 subjects (98 h of recording) and panel B results from 6 subjects (120 h of recording]. In the bottom panel, the dark hatched lower portions show phase III (MMCs) that could be traced all the way from the proximal sensor; the lighter crosshatching portions are MMC-like “fronts” that commenced distally.
shows the same overall organization as in humans, >80% of MMCs reach the ICS (30). Two additional points are of note. As shown in Figure 8, those phase III fronts that could be traced from the most proximal sensor usually “faded out” in the ileum; however, additional motor patterns with characteristics similar to MMCs originated distally. Migrating motor complexes begin usually in the foregut, but a proportion also appear to start in the jejunum; indeed, some feel that the controlling mechanisms for these two phenomena are different (31). We noted jejunal, but not ileal, starting points for MMCs previously (17) and the significance of their origin in the ileum is unknown. It must also be recognized that any prolonged intubation creates variable and uncertain degrees of sleeving of bowel over tube. Thus, our definitions of distance refer to lengths of tubing and extrapolations to lengths of bowel should be guarded. The second pattern of motility we saw could be best categorized as “discrete clustered contractions,” a phenomenon that may be the ileal equivalent of “clustered” contractions in the jejunum (32) or “minute rhythms” of the jejunum and ileum (33). Descriptively, our recordings featured frequent groupings of lo-20 phasic contractions, occurring at the frequency of the slow wave at the particular intestinal locus. This varied from 10 to 12imin in the proximal leads to 7-8/min at the ICS. For these groupings of contractions to be identified with certainty, periods of relative quiescence needed to be motility
Vol. 87, No. 4
present before and after. Thus, though we noted considerable variation among individuals in their prevalence, this should be interpreted cautiously. It is possible that grouped contractions were masked in some individuals when the background featured many random contractions (Figure 3). Nevertheless, in those individuals showing the clearest patterns, clusters occurred at a frequency of 30-40/h, or approximately one every 2 min. Propagation of this contractile sequence was also difficult to define. We chose to underestimate intentionally any temporal relationship that might exist between bursts in adjacent tracings (Figure 5) but, notwithstanding, could classify -20% of these patterns as being propagated, for distances of >50 cm at times. The third striking phenomenon was a broad phasic wave of pressure that propagated rapidly (“prolonged propagated contraction”). Each of these events lasted longer than the ileal slow wave (6-8 s), often exceeding 30 s in duration and the pressures developed were often large (~50, and up to 100 mmHg). Their propagation was extremely rapid. Thus, MMCs traversed the terminal ileum at rates of 0.7-3.0 cm/min, whereas the broad pressure waves propagated at 60 cm/min. Though this contractile pattern appears not to have been recorded before in healthy humans, its mechanical and electrical equivalents have been described in the dog (14,31). Moreover, these “peristaltic” sequences propel fluid and empty the canine ileum (14). An equivalent, prolonged, propulsive motor event (“type IV contraction”) was described by Code et al. (34), recording from large balloons placed proximal to ileostomies. We have recorded similar pressure waves from the ileum used to fashion a “neorectum” after ileoanal pull-through operations (35). Thus, it is likely that such contractions occur infrequently in the healthy human ileum but can be evoked by distention, as in the dog (14). Moreover, this unique motor property of the terminal ileum has a characteristic electrical equivalent in the dog (14). Indeed, this electrical signal is similar to the rapidly propagated spike bursts that occur when the rabbit ileum is distended (36) or exposed to bacterial toxins and other diarrheogenic agents (37,381. Isolated preparations of the ileocecal junction in the dog (5) and humans (6) show a zone of tonic pressure across the sphincter. Our own studies in the dog revealed tonic pressures of 20-30 cmH20 at the sphincter, especially when phasic contractions traversed the region (12,31). In humans, we recorded pressures in excess of 20 mmHg on a few occasions, but only when the sphincter was contracting phasitally. When phasic waves were absent, resting pressures at the sphincter were the same as baseline. We recorded similar slight elevations of tone when pha-
October
1984
sic contractions traversed the terminal ileum at a distance from the ICS. For these reasons, we believe that high tonic pressure may not be a feature of the human ICS. However, it must be appreciated that our system did not permit “pull-through profiles” to be recorded. On the other hand, it seems unlikely, that our closely spaced (1.5-cm intervals] sensors failed to register high, tonic, sphincteric pressures in >lOO h of recording from 16 subjects should such exist in the healthy intact bowel. In perspective, these descriptive studies need the context of parallel observations in other systems. Weems and Seygal (39) have argued convincingly that the terminal ileum has special properties, the most dramatic being its ability to develop high hydrostatic pressures. Our data support and perhaps give a basis for these observations; prolonged, propulsive contractions could provide such a force if they are stimulated in other species by distention as they are in the dog (14). Thus, the ileocecal segment might develop forces necessary for “systolic” propulsion, a concept that has been applied to another junctional zone, the sphincter of Oddi of the opossum (40). Furthermore, the implications of coordinated ileocecal transit are considerable. Thus, when the human colon is overloaded with fluid by brief, rapid infusions, its absorptive capacity is readily surpassed (10,ll). Because ileocecal muscle behaves as a sphincter (7-g), we were surprised by the absence of clear tonic pressures across the ICS. However, the cecum and ileum could be compartmentalized adequately, even by the low and intermittent pressures we recorded. Given that the cecum and ileum are within a common chamber of pressure, the peritoneal cavity, a small pressure differential might suffice to separate cecal flora from the relative sterility of the small bowel. Moreover, the potential of propagated contractions to empty the terminal ileum offers a mechanism for effectively clearing the ileum of reflux. Finally, we are confident that the major features of our findings are not the result of artifacts introduced by intraluminal sensors. We have recorded identical patterns in the dog, using intraluminal sensors in some animals but extraluminal strain gauges and serosal electrodes only in others (12,30). Thus, we feel that motility patterns from the terminal ileum, across the ICS, and from the cecum can be recorded reproducibly in healthy humans. The region’s motility demonstrates sufficient functional specialization to warrant further exploration. References 1. Krag E, Phillips
SF. Active and passive bile acid absorption in man: perfusion studies of the ileum and jejunum. 1Clin Invest 1974:53:1686-94.
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RM Jr, Mackenzie IL. Trier JS. Intrinsic factor2. Donaldson mediated attachment of vitamin Br3 to brush border and microvillus membranes of hamster intestine. J Clin Invest 1967;46:1211-5. 3. Gorbach SL, Plant AG. Nahas L, Weinstein L. Spanknebel G. Levitan R. Studies of intestinal microflora. II. Microorganisms of the small intestine and their relationship to oral and fecal flora. Gastroenterology 1967:53:856-67. 4. Donaldson RM. Toskes PP. The relation of enteric bacterial population to gastrointestinal function and disease. In: Sleisenger MH, Fordtran JS. eds. Gastrointestinal disease. Philadelphia: WB Saunders, 1983:544-54. 5. Kelley ML Jr, DeWeese JA. Effects of eating and intraluminal filling on ileocolonic functional zone pressure. Am J Physiol 1969:216:1491-5. 6. Cohen S, Harris LD. Levitan R. Manometric characteristics of the human ileocecal functional zone. Gastroenterology 1968;54:72-5. JL, Christensen J. Local specialization at ileocecal 7. Conklin junction of the cat and opossum. Am J Physiol 1975: 228:1075-81. J, Snape WJ Jr, Cohen S. Adrenergic a. Rubin MR, Fournet regulation of ileocecal sphincter function in the cat. Gastroenterology 1980;78:15-21. 9. Owyang A, Clain CJ, Snape WJ Jr. Cohen S. Characterization of opiate-mediated responses of the feline ileum and ileocecal sphincter. J Clin Invest 1982;69:507-15. of the colon to electro10. Phillips SF, Giller J. The contribution lyte and water conservation in man. J Lab Clin Med 1973;81:733-46. JC, Phillips SF. Capacity of the human colon to 11. Debongnie absorb fluid. Gastroenterology 1978:74:698-703. EMM. Phillips SF, Dent J. Taylor BM. Myoelectric 12. Quigley activity and intraluminal pressure at the canine ileocolonic sphincter. Gastroenterology 1983;85:1054-62. SF. Interdigestive patterns of intralu13. Quigley EMM. Phillips minal pressure at the canine ileocolonic junction (abstr). Gastroenterology. 1983;84:1279. F, Phillips SF. High pressure propulsive 14. Kruis W. Azpiroz forces of the canine ileum. Clin Ros 1983;31:764A. W. The Huxtley lecture on the function of the 15. Macewen cecum and appendix. Lancet 1904:ii:995-1000. B. Harris AS. Observations 16. White HL, Rainey WR. Monaghan on nervous control of ileocaecal sphincter and on intestinal movements in unanaesthetised human subjects. Am J Physiol 1934:108:449-57. of motility of the ileum and 17. Kerlin P, Phillips SF. Variability jejunum in healthy man. Gastroenterology 1982;82:694-700. A, Phillips SF. Relationship of motility 18. Kerlin P. Zinsmeister to flow of contents in the human small intestine. Gastroenterology 1982;82:701-6. A, Phillips SF. Motor responses to food 19. Kerlin P, Zinsmeister of the ileum, proximal colon, and distal colon of healthy humans. Gastroenterology 1983;84:762-70. SF. Differential transit of liquids and solid 20. Kerlin P, Phillips residue through the human ileum. Am J Physiol 1983:8:G3843. SF, Wienbeck M, Tucker RL. Fasting 21 Quigley EMM. Phillips patterns of motility at the ileocolonic junction in normal man (abstr). Gastroenterology 1983;84: 1279. EMM, Phillips SF, Weinbeck M, Haddad AC. The 22. Quigley effect of morphine on motility, flow and transit in the human ileocolonic junctional region labstr). Gastro Clin Biol 1983:7:727. SF. Rapid intubation of the ileo23. Kerlin P. Tucker R, Phillips colonic region of man. Aust NZ J Med 1983;13:591. RC, Stef JJ. Dodds WJ. Linehan JH. Hogan WJ. 24. Arndorfer
866
25. 26. 27. 28. 29.
30.
31. 32.
33. 34.
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GASTROENTEROLOGY
ET AL.
Improved infusion system for intraluminal esophageal manometry. Gastroenterology 1977;73:23-7. Hertz AF. The ileo-caecal sphincter. J Physiol 1903;47:54-6. Caste11 DO, Cohen S. Harris LD. Response of the human ileocecal sphincter to gastrin. Am J Physiol 1970;219:712-5. Szurszewski JH. A migrating electric complex of the canine small intestine. Am J Physiol 1969:217:1757-63. Wingate DL. Backwards and forwards with the migrating complex. Dig Dis Sci 1981;26:641-66. Rayner V, Weekes TEC, Bruce JB. Insulin and myoelectric activity of the small intestine of the pig. Dig Dis Sci 1981:26:33-41. Quigley EMM. Phillips SF, Dent J. Distinctive patterns of interdigestive motility at the canine ileocolonic junction. Gastroenterology 1984;87:836-44. Wingate DL. Complex clocks. Dig Dis Sci 1983:28:1133-40. Summers RW, Anuras S, Green J. Jejunal manometry patterns in healthy, partial intestinal obstruction and pseudoobstruction. Gastroenterology 1983;85:1290-300. Fleckenstein P. Migrating electrical spike activity in the fasting human small intestine. Am J Dig Dis 1978:23:769-75. Code CF, Rogers AG, Schlegel J, Hightower NC, Bargen JA. Motility patterns in the terminal ileum: studies in two pa-
35.
36.
37.
38.
39.
40.
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tients with ulcerative colitis and ileal stomas. Gastroenterology 1957;32:651-65. Heppell J, Pemberton JH, Kelly KA, Phillips SF. Ileal motility after endorectal ileoanal anastomosis. Surg Gastroenterol 1982;1:123-7. Sjogren RW, Wardlow M, Charles LG. Stimulation of action potential complexes by fluid distention of the rabbit small intestine. Evidence that migrating action potential complexes (MAPC) are a non-specific myoelectric response (abstr). Gastro Clin Biol 1983;7:728. Mathias JR, Carlson GM, DiMarino AJ. Bertiger G, Morton ME, Cohen S. Intestinal myoelectric activity in response to live vibriocholerae and cholera enterotoxin. J Clin Invest 1976: 58:91-6. Mathias JR, Martin JL, Burns TW, Carlson GH, Shields RP. Ricinoleic acid effects on the electrical activity of the small intestine in rabbits. J Clin Invest 1978:61:640-4. Weems WA, Seygal GE. Fluid propulsion by cat intestinal segments under conditions requiring hydrostatic work. Am J Physiol 1981;G147-56. Toouli J, Dodds WJ, Honda R, et al. Motor function of the opossum sphincter of Oddi. J Clin Invest 1983;71:208-20.
1984;87:857-66
Motility of the Terminal Ileum and Ileocecal Sphincter in Healthy Humans E. M. M. QUIGLEY, T. J. BORODY, M. WIENBECK, R. L. TUCKER, and Gastroenterology
Unit, Mayo Clinic,
Rochester,
Factors controlling the transit of contents between the ileum and cecum should be important determinants of intestinal function; however, the dynamics of the ileocecal region remain largely unexplored in healthy humans. Accordingly, prolonged recordings of intraluminal pressure were obtained from the distal ileum, across the ileocecal sphincter, and from the proximal colon of healthy adults. In one set of studies, 16 subjects each contributed 6 h of basal, fasting recordings; in 2 of the 16, postprandial patterns were also recorded. In a second set, 6 fasting subjects were studied for a total of 120 h. Less than 10% of interdigestive cycles (migrating motor complexes) reached the ileocecal sphincter. The remainder faded out and merged into an active, apparently random pattern of pressure waves that became more intense closer to the sphincter. Discrete, short bursts of phasic pressures migrated rapidly for long distances in the distal ileum and a unique peristaltic wave also migrated rapidly, though infrequently, through the region. Tonic pressures were recorded across the ileocecal sphincter but were present only during the passage of phasic
Received January 27, 1984. Accepted April 17, 1984. Address requests for reprints to: Sidney F. Phillips, M.D., Gastroenterology Unit, Mayo Clinic, Rochester, Minnesota 55905. E. M. M. Quigley’s present address is University Department of Medicine, Hope Hospital, Eccles Old Road, Salford M6 8HD, United Kingdom. This study was supported in part by Grants RR00585 and AM32121 from the National Institutes of Health, Bethesda, Maryland. Dr. Quigley was an International Research Fellow of the Fogarty Foundation (TWO 3117). Dr. Borody was supported by a Neil Hamilton Fairley Fellowship from the National Health and Medical Research Council (Australia). Dr. Wienbeck was supported by a grant from the Minister fuer Wissenschaft und Forschung in Nordrhein-Westfalen (Federal Republic of Germany). The authors thank the nurses of the General Clinical Research Center, Mayo Foundation for their help with these studies and Mrs. Deborah Frank for expert secretarial assistance. 0 1984 by the American Gastroenterological Association 0016-5085/84/$3.00
S. F. PHILLIPS, A. HADDAD
Minnesota
pressure waves; basal tone was minimal. We believe these are the first prolonged observations of motility from the ileocecal sphincter of healthy humans. These descriptions provide insights into and a basis for further studies of a largely unexplored area of the human bowel. The junction between the ileum and colon is the least explored site of the gastrointestinal tract, and yet it probably represents an important transition zone. Some functions of the ileum are quite specialized, active absorption of bile acids (I) and of vitamin B12 (2) being the most obvious examples. In addition, the ileocecal junction separates the abundant and complex flora of the large bowel from the less contaminated ileum (3), and the consequences of bacterial overgrowth in the small bowel are well recognized (4). Thus, the large and small bowels are compartmentalized by the ileocecal junction which in the dog (5) and humans (6) exhibits a segment of “tonic” pressure; the zone relaxes with distention of the ileum and contracts with distention of the proximal colon. These characteristic properties of a “sphincter” are supported further by the unique cellular properties of muscle from the junctional zone (7) of the cat, including specific responses to pharmacologic agents (8,9). A second possible function of the ileocecal junction is any influence it may have on the transit of thyme from ileum to colon. The human colon absorbs up to 1500 ml of thyme daily (lo), a value that can be increased threefold to fourfold under appropriate conditions of loading (11). The rapid infusion of fluid into the cecum (ll), however, impairs transiently the capacity of the colon to compensate. Thus, transit of fluid from ileum to colon, as influenced by patterns of motility, has the potential of influencing the colon’s ability to respond to increased loads. Abbreviations MMC. migrating
used in this paper: motor complex.
ICS,
ileocecal
sphincter:
858
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ET AL.
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We have established that the canine ileocolonic junction has a motor pattern that varies cyclically during fasting (12,13),with cycles of interdigestive motor activity passing through the terminal ileum as far as the ileocolonic sphincter (12). Thus, an understanding of the dynamic functions of this region requires prolonged observations that can appreciate cycles of activity that have a periodicity of l-2 h. Furthermore, the canine ileum can propel contents fashion (13,14). Prominent high in a “peristaltic” pressure contractions, which are propagated rapidly, constitute an effective mechanism for emptying loops of canine ileum (14). Further exploration of this region in intact humans seemed worthwhile, as reports of its functional characteristics are confined currently to the simplest of observations (15,16). The present study was designed to evaluate, by measurements of intraluminal pressure, the motor patterns of the terminal ileum, ileocecal sphincter (ICS), and cecum in intact humans. It was our intent to extend our earlier observations in the dog (12-14) as well as those on motility and flow in the terminal ileum of humans (17-20).
Material and Methods
Vol.
87.
No. 4
included also one or two radiopaque tubes (Ferraris Engineering, Edmonton N18. London. England), one of which ran the length of the assembly. This facilitated localization of the tube fluoroscopically and also served to inflate with air a balloon that surrounded the terminal mercury weight. Inflation of the balloon speeded passage of the assembly through the bowel (23). The balloon was deflated when the assembly reached the cecum. Location of the tube was by and end of each fluoroscopy (Figure 1) at the beginning study, and by visual inspection of tracings during the recording sessions. Thus, the characteristic frequencies of phasic pressure waves in the ileum and colon could be
recognized [Figure 2). Recording lumens were perfused with water by a low compliance system (24), the details and validation of which have been reported previously (17). Pressures from the perfused catheters were recorded. via transducers (Statham-Gould, P-23, Statham Instruments, Inc., Halto Rey, Puerto Rico), by two synchronized multichannel recorders (MFE 1600). The technique was acceptably comfortable for most volunteers; 26 individuals were intubated for a total of 22 successful experiments. In the first 16 subjects (group A), intraluminal pressures were measured from the terminal 30-50 cm of ileum, across the ICS, and from the proximal colon. The sensors were located (in centimeters from the aborad end of the tube) at 0, 5, 6.5, 8.0, 9.5, 11.0, 12.5. 17.5, 22.5, 37.5, and 52.5 cm. Thus, when the terminal sensor was in the proximal colon, the closely spaced array of sensors straddled the ileocecal junction (Figure 1). It was not possible to
Two sets of studies on healthy, adult volunteers are reported. None had symptoms or a past history of significant gastrointestinal disease and all gave written informed consent for the protocols that were approved by the Mayo Clinic’s Human Studies and Radiation Control Committees. The first group of 16 subjects (11 men, 5 women; aged 20-71 yr) participated in a 24-h study that included observations of the effects of drugs on ileocecal motility, the details of which will not be included here. These have been described in abstract form elsewhere (21,22). However, as part of the study, a 6-h recording of basal, fasting motility (before the administration of any drugs) was available from each subject. It is these recordings that form the basis of the present results. Two of the 16 subjects received placebo drugs throughout the 24-h study and were also given a mixed meal of 600 kcal (40: 40: 20; fat/carbohydrate/protein); 12 h of postprandial recording were available in these subjects. A second group of 6 subjects (4 men, 2 women; aged 20-47 yr) were studied with a different recording system for 18-22 h fasting, and without the administration of drugs.
IntraJuminaJ
Sensors
and
Study
Design
Intraluminal pressures were recorded from opentips cut into an array of polyvinyl tubes (Dural Plastics, Dural 2158, New South Wales, Australia). Each component tube had an external diameter of 2.0 mm and featured three individual lumens, of internal diameter 0.78 mm. The composite assembly, of three triple-lumen tubes, was prepared locally by gluing the components together. We
Figure
1. Radiograph of tube assembly in position. Sites open-tip sensors are indicated by small metal The closely spaced sensors straddle the ileocecal tion.
of the plugs. junc-
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MOTILITY OF ILEOCECAL REGION
1984
TERMINAL ILEUM (30 cm from ICS)
9.25 min-’ ILEOCECAL SPHINCTER
6 min-’ Figure 2. Compendium recording from 1 subject showing phasic waves at the maximum rate for each locus: i.e.. the frequency of the corresponding slow wave (BER or ECA). The ileal frequency, 8-10 min- I, can be distinguished from that at the ileocecal sphincter (ICS). 7-8 min ‘, and the cecum. 6-7 min ‘. The time bars are of 2 min.
obtain exactly the same tube position in all subjects. However, by fluoroscopy, before and after the study, and by visual counting of contractile frequencies (Figure 2). the position of the ileocecal junction could be localized to within l-3 cm of tubing. We report here a total of 98 h of fasting recording from these 16 subjects. In the second set of six studies (group B), the locations of the side-hole sensors were different. They were at 0, 10, 20, 30,40, 50, 75, 100, and 125 cm from the aborad end of the tube. The assembly was passed 10-30 cm into the colon. so that the more proximal sensors spanned -100 cm of ileum. A total of 120 h of fasting recording was accumulated from 6 subjects. Our aim here was to examine fasting patterns of motility over the distal 100 cm of small bowel, whereas in the first set of experiments, the sensors were located within the terminal 40-50 cm of ileum, with the ICS receiving particular attention.
Motility Patterns-Definitions Statistical Evaluation
and
Records were analyzed visually, by at least two observers who agreed as to the presence of the various motor patterns. For phase III of the migrating motor complex (MMC) to be defined required the presence of 3 min of uninterrupted, phasic pressures at the maximum frequency (7-llimin) for that locus of the small bowel (17). Phasic contractions in the proximal colon were slower (maximum Gimin) than in the ileum. To be catego-
rized as progressive, phase III needed to be recorded sequentially in three adjacent channels or from the two most proximal channels. When rhythmic bursts of phasic contractions of shorter duration (~3 min) were recorded, they were designated as “discrete clustered contractions.” These were most prominent in the upper ileum, some being propagated between adjacent sites, but others could
IN
HlJMANS
859
easily be seen to propagate. For the recognition of patterns and for the counting of total contractile events, pressure waves under 8 mmHg in amplitude were ignored
not
because it was difficult at times to distinguish these lesser amplitudes from respiratory excursions. Single pressure waves, which had a duration longer than the ileal slow wave (6-8 s), often lasting more than 30 s, and sometimes achieving pressures in excess of 100 mmHg, were seen to propagate rapidly through the distal ileum. These were designated as “prolonged propagated contractions.” Tonic pressures at the ICS were measured from the “trough” of phasic contractions to baseline pressure. in the sensor judged to be closest to the sphincter segment. For comparisons, the same measurements were made on simultaneous recordings from an ileal sensor located away from the KS. Where appropriate, statistical comparisons were made by paired or unpaired t-tests.
Results Positioning
of Tubes
Assemblies passed into place usually in 6-8 h. The mean length of tubing needed to reach the cecum was 208 cm (178-240 cm) beyond the teeth. Subjects tolerated the study well, sleeping during the overnight phase. Tubes were well maintained in place after deflation of the terminal balloon, a few centimeters of progression further into the colon being sometimes noted at the final fluoroscopy. In 4 subjects, the assembly did not cross the ileocecal junction or inspection of recordings suggested advancement of the tube far into the colon; interim fluoroscopy and retrieval of tubing was then required. These studies were discarded. A few subjects noted mild nausea or discomfort within the throat, but no other side effects were reported or observed.
Overall
Patterns
of Motility
Much of the time, recordings displayed an apparently random pattern of ileal contractions (Figure 3), similar to that reported for phase II at other loci in the small bowel (17). This pattern of random contractions became more intense (i.e., showed more contractile activity per unit time) close to the ileocecal junction. Superimposed upon these random contractions were the more organized patterns, phase III of the MMC (Figures 3 and 4) and discrete clustered bursts [Figures 3 and 5), as well as prolonged propagated contractions (Figure 6). A gradient in the prevalence of random contractile activity along the terminal ileum was quantified in group B. All contractile events were counted at different loci for one interdigestive cycle in each subject (excluding phase III). The number of contractions increased twofold to fivefold between the most
860
QUIGLEY ET AL.
GASTROENTEROLOGY
Vol. 87, No. 4
orad sidehole (-100 cm proximal to the ICS) and the side hole closest to the junction (Figure 7). Migrating Motor Complexes Phase III of the interdigestive cycle (MMC) was recognized in the terminal ileum and occasionally was seen to involve the ICS and cecum. Figure 4 shows clearly a burst of phase III activity passing through the terminal ileum, across the ICS, and into the cecum. Such progression, however, was unusual. More often, phase III activity fronts became attenuated toward the ICS; they were less well defined, and not so well demarcated by a subsequent period of phase I quiescence (Figure 3). Thus, in 98 h of recording from the 16 studies in group A, only three typical phase III patterns were identified. It was this finding that prompted the design of the group B studies in which phase III activity was sought over a longer segment of ileum. In 120 h of recording from the second group of studies, the attenuation of phase III activity toward the ICS could be quantified (Table 1).Only one-third of the phase III activity fronts identified in the proximal sensor reached a point 40 cm from the ICS and only 2% reached the ICS. Other “MMC-like” patterns were seen in the ileum but these appeared to originate these for they could not be linked to “fronts” passing into the upper ileum from above. Table 1 also demonstrates that the MMC slows and lengthens toward the ICS. Discrete Clustered
Contractions
This pattern encompassed bursts of phasic contractions at the rate of slow waves for each level of the small bowel. Their durations were shorter than those of the MCCs; they lasted 20-80 s (mean 44 s). These grouped waves were variably present among individuals (Table 2).In some tracings, they were very prominent (Figure 5) and when well developed, they appeared rhythmic with a periodicity between 31 and 46/h (mean 36/h). It was often not possible to define the propagation of these patterns precisely. In some instances, propagation over three sequential recording sites was clear (Figure 5), but on other occasions the presence of intense random contractions may have obscured any propagation. In the most obvious examples, propagation was rapid, 30-250 cm/min (mean -120 cm/min) and over distances in excess of 50 cm. Prolonged
Propagated
Contractions
These striking
waves were of long duration amplitude (50variability was again noted; some persons having none during 6 h of (12-40 s) and often of considerable 100 mmHg) (Figure 6). Individual
October
1984
MOTILITY
OF ILEOCECAL
REGION
IN HUMANS
861
Terminal Ileum
ICS Colon
Figure
4. Recording of intraluminal pressures from the human ileum, ileocecal progression of phase III down to, and through. the ileocecal sphincter: terminal ileum (compare with Figure 3).
recording and 1 person having up to 3 per hour. These waves propagated rapidly (20-120 cm/min, mean -60 cmimin), were seen predominantly in the distal 20-30 cm of ileum, and some crossed the ICS. Figure 6 (right panel) shows also that phasic activity may follow the prominent, single wave. Tonic Pressures
at the Ileocecal
sphincter (ICS). and cecum. This example this was an unusual event, phase III usually
shows clear faded in the
was present for the majority of recording time and tonic elevation of the baseline was present only during times of sustained phasic contractions at the
Sphincter
Tone was present only intermittently at the ICS. When records from the sensor(s) judged to be closest to the ICS were examined, no tonic pressure
Distance from ICS
35 cm A--. \ \
25 cm * 15 cm W
Figure
11
--
.. .s
5. Recording of intraluminal pressure from ileum, ileocecal sphincter (ICS), and cecum of a healthy record are groups of phasic contractions (“discrete clustered contractions”) that appear at a frequency min. ‘The dotted lines are arbitrarily drawn and represent only one possible pattern of propagation.
adult. Prominent in this of about one burst per 2
862
QUIGLEY
ET AL.
GASTROENTEROLOGY
5OmmHg b mln
cm Figure
6. Recording of intraluminal pressure from ileum, ileocecal sphincter (ICS). and cecum of a healthy adult. Prominent phasic contractions that last 20-40 s, and that are propagated rapidly down to the ileocecal sphincter (‘*prolonged contractions”]. Though usually single, some examples are followed by (right panel) repetitive, phasic waves.
Postprandial
Patterns
Twelve hours of recording are reported from 2 subjects in group A who received only placebo drugs. The usual pattern of intense random contractions (“fed pattern”) was seen. No MMCs, discrete
\ t \\ \ f
01
’
I
I
125
90
55 -Ileum
I
I
I
I
I
I
40 30 20 10 0 -10 Teninal ileum ICS Colon
Position of sensor Figure
Vol. 87. No. 4
(CM proZel.sICS)
7. Total number of contractions at various loci of the distal ileum. The numbers of single contractile events were those occurring after the end of one phase III burst (migrating motor complex, MMC) up to the beginning of the next. When MMCs were not present in those recordings from close to the ileocecal sphincter (ICS), an equivalent recording time to that evaluated proximally was used. The total number of pressure waves increases severalfold up to the ICS. (n = 6 subjects, vertical bars = SEM.)
clusters, or prolonged identified.
propagated
are single, propagated
contractions
were
Discussion Certain functions of the ileocecal region in humans were observed grossly and reported early in the century (15,16,25). When seen through intestinal stomas, a consistent feature was that thyme was expelled intermittently and forcefully from the ileum. These findings suggested that ileocecal motility was coordinated and that the terminal ileum could develop powerful propulsive (“peristaltic”) forces. These early observers also noted that ileal peristalsis “frequently fails to reach the sphincter” (16)and occurs once or twice per hour (15,16,25); in addition, radiopaque food was often stored in the ileum (25). The possibility is raised, therefore, of incomplete emptying and storage of content by the ileum. The human ileocecal sphincter was first studied quantitatively by Cohen and his colleagues (6,26). They took the opportunity offered by patients who had their colons defunctioned surgically for the treatment of portosystemic encephalo,pathy. They performed “pull-throughs” across the sphincter, and confirmed the findings of Kelley and DeWeese (5) in the dog. A mean tonic pressure of 20 cmH,O could be recorded over a distance of 4 cm; basal pressures were augmented by cecal distention and reduced by ileal distention (6). They also evaluated the influ-
October
Table
MOTILITY
1984
1. Occurrence
of Phase
III Contractions
(Migrating
OF ILEOCECAL REGION IN HUMANS
a63
in Human Ileum and Its Relationship to
Motor Complexes)
Ileocecal Topography Phase Approximate location of sensor”
Sensor No.
Total No.
115 90 65 40 30 20 10 ICS Colon ICS, ileocecal
sphincter:
motor
9.3 10.0 13.7 17.2 la.3 20.2 17.2 18.8
complex.
of gastrin on the sphincter (26); exogenous gastrin or alkalinization of the antrum reduced sphincteric tone. After these reports, the region remained largely unexplored in humans until it became possible to record accurately intraileal pressures (171, using fine, multilumen flexible catheters, and using sensitive, reliable low compliance systems (24). The present studies were further facilitated by tube assemblies that enabled the ileocolonic region to be intubated rapidly and reproducibly (23). Using these approaches, it was possible for the first time to observe patterns of motility in the healthy terminal ileum, ICS, and cecum. Our first important finding was that it was distinctly unusual for the MMC (phase III of the interdigestive, myoelectric complex, “activity front”) in humans to traverse the entire terminal ileum, through to the ICS. Though we recorded examples of an MMC progressing into the colon (Figure 4), these were the exceptions. More often, phase III sequences became unrecognizable within the apparently random activity that predominated in the distal ileum. The electrical equivalent of the MMC, as first described in dogs, traversed the entire small bowel (27) and, in other species, MMCs are assumed to progress to the ileocecal junction (28). However, the pig’s
2. Characteristics
of Discrete
Duration of record Subject 1
19
22 15 22 23 21
a Range
Total No.
(hl
2 3 4 5 6 20-80
s. ” Range
Clustered
417 3 a9 a5 175 294 30-250
cmimin.
’Obvious
Contractions
proximal
to ileocecal
k -+ + t -c f 2 2
Maximum phasic rate” (min I)
0.6 0.2 0.4 0.5 0.9 1.6 0.2 0.2
11.9 t 0.3 10.9 t 0.3
10.4 9.8 9.6 a.8 8.6 8.0 6.9
sphincter.
” Mean
-+ + + -t + t +
0.3 0.2 0.3 0.3 0.4 0.6 0.3
k SEM
small bowel is similar to that of humans; in one report (29), 35% of MMCs were not conducted over the entire small bowel, but “disappeared” in the ileum. Our figure for attenuated MMCs is larger in humans (?90%), recalling the earlier report of “peristalsis” often failing to reach the sphincter in 1 patient (16). Previously, we (17) have described ileal MMCs as occurring with the same cycle length as those of the proximal small bowel; in other words, Kerlin and Phillips (17) did not note that phase III disappeared in the terminal ileum. The results of experiments in series A, in which phase III was an infrequent event (3 MMCs in 98 h), were in sharp contrast to our earlier findings (17) of 18 MMCs in 37 h of recording. This surprising disparity was the rationale for the experiments of group B. Thus, in the study by Kerlin and Phillips (171, the most distal sensors were usually 20-30 cm orad to the ileocecal junction, whereas in the group A studies, the most proximal sensors were 40-50 cm orad to the ICS. The experiments .of group B, which traced MMCs over a loo-cm segment of terminal ileum, showed clearly that many human MMCs, like those of the pig, disappear in the terminal ileum (Figure 8). Differences among species are highlighted further by our own results in the dog: although ileocolonic
in Human
Mean duration”
Ileum
No. showing clear propagation
Lsl 41 42 46 43 47 46 progression
3.1 1.5 1.2 1.0 1.6 1.4 0.6 0.7
f 1.7 f 2.2 2 2.0 -’ 4.0 t 4.5 -c 4.2 2 7.8 + 12.0 16.2
” In centimeters
ence
Table
Velocity between adjacent sensors”(cm/min)
Duration” (min)
a5 60 48 29 12 a 4 3 2
MMC. migrating
III (MMCs)
128
9 24 35 not noted
in these
subjects.
Velocity” (cm/min]
Minimal distance traversed (cm]
1 o-1
56
125 101 46
63 65 57
864
QLJIGLEY ET AL.
GASTROENTEROLOGY
n=16 6’6 h
recording
122 h recording
B
120
90
Distance
60
from ICS - cm
40
30
20
10
TR'emu';6i
0 IES
-10 Colon
Figure 8. Topographic distribution of the occurrence of MMCs at different levels of the ileum, ileocecal junction, and cecum. Panel A shows results from 16 subjects (98 h of recording) and panel B results from 6 subjects (120 h of recording]. In the bottom panel, the dark hatched lower portions show phase III (MMCs) that could be traced all the way from the proximal sensor; the lighter crosshatching portions are MMC-like “fronts” that commenced distally.
shows the same overall organization as in humans, >80% of MMCs reach the ICS (30). Two additional points are of note. As shown in Figure 8, those phase III fronts that could be traced from the most proximal sensor usually “faded out” in the ileum; however, additional motor patterns with characteristics similar to MMCs originated distally. Migrating motor complexes begin usually in the foregut, but a proportion also appear to start in the jejunum; indeed, some feel that the controlling mechanisms for these two phenomena are different (31). We noted jejunal, but not ileal, starting points for MMCs previously (17) and the significance of their origin in the ileum is unknown. It must also be recognized that any prolonged intubation creates variable and uncertain degrees of sleeving of bowel over tube. Thus, our definitions of distance refer to lengths of tubing and extrapolations to lengths of bowel should be guarded. The second pattern of motility we saw could be best categorized as “discrete clustered contractions,” a phenomenon that may be the ileal equivalent of “clustered” contractions in the jejunum (32) or “minute rhythms” of the jejunum and ileum (33). Descriptively, our recordings featured frequent groupings of lo-20 phasic contractions, occurring at the frequency of the slow wave at the particular intestinal locus. This varied from 10 to 12imin in the proximal leads to 7-8/min at the ICS. For these groupings of contractions to be identified with certainty, periods of relative quiescence needed to be motility
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present before and after. Thus, though we noted considerable variation among individuals in their prevalence, this should be interpreted cautiously. It is possible that grouped contractions were masked in some individuals when the background featured many random contractions (Figure 3). Nevertheless, in those individuals showing the clearest patterns, clusters occurred at a frequency of 30-40/h, or approximately one every 2 min. Propagation of this contractile sequence was also difficult to define. We chose to underestimate intentionally any temporal relationship that might exist between bursts in adjacent tracings (Figure 5) but, notwithstanding, could classify -20% of these patterns as being propagated, for distances of >50 cm at times. The third striking phenomenon was a broad phasic wave of pressure that propagated rapidly (“prolonged propagated contraction”). Each of these events lasted longer than the ileal slow wave (6-8 s), often exceeding 30 s in duration and the pressures developed were often large (~50, and up to 100 mmHg). Their propagation was extremely rapid. Thus, MMCs traversed the terminal ileum at rates of 0.7-3.0 cm/min, whereas the broad pressure waves propagated at 60 cm/min. Though this contractile pattern appears not to have been recorded before in healthy humans, its mechanical and electrical equivalents have been described in the dog (14,31). Moreover, these “peristaltic” sequences propel fluid and empty the canine ileum (14). An equivalent, prolonged, propulsive motor event (“type IV contraction”) was described by Code et al. (34), recording from large balloons placed proximal to ileostomies. We have recorded similar pressure waves from the ileum used to fashion a “neorectum” after ileoanal pull-through operations (35). Thus, it is likely that such contractions occur infrequently in the healthy human ileum but can be evoked by distention, as in the dog (14). Moreover, this unique motor property of the terminal ileum has a characteristic electrical equivalent in the dog (14). Indeed, this electrical signal is similar to the rapidly propagated spike bursts that occur when the rabbit ileum is distended (36) or exposed to bacterial toxins and other diarrheogenic agents (37,381. Isolated preparations of the ileocecal junction in the dog (5) and humans (6) show a zone of tonic pressure across the sphincter. Our own studies in the dog revealed tonic pressures of 20-30 cmH20 at the sphincter, especially when phasic contractions traversed the region (12,31). In humans, we recorded pressures in excess of 20 mmHg on a few occasions, but only when the sphincter was contracting phasitally. When phasic waves were absent, resting pressures at the sphincter were the same as baseline. We recorded similar slight elevations of tone when pha-
October
1984
sic contractions traversed the terminal ileum at a distance from the ICS. For these reasons, we believe that high tonic pressure may not be a feature of the human ICS. However, it must be appreciated that our system did not permit “pull-through profiles” to be recorded. On the other hand, it seems unlikely, that our closely spaced (1.5-cm intervals] sensors failed to register high, tonic, sphincteric pressures in >lOO h of recording from 16 subjects should such exist in the healthy intact bowel. In perspective, these descriptive studies need the context of parallel observations in other systems. Weems and Seygal (39) have argued convincingly that the terminal ileum has special properties, the most dramatic being its ability to develop high hydrostatic pressures. Our data support and perhaps give a basis for these observations; prolonged, propulsive contractions could provide such a force if they are stimulated in other species by distention as they are in the dog (14). Thus, the ileocecal segment might develop forces necessary for “systolic” propulsion, a concept that has been applied to another junctional zone, the sphincter of Oddi of the opossum (40). Furthermore, the implications of coordinated ileocecal transit are considerable. Thus, when the human colon is overloaded with fluid by brief, rapid infusions, its absorptive capacity is readily surpassed (10,ll). Because ileocecal muscle behaves as a sphincter (7-g), we were surprised by the absence of clear tonic pressures across the ICS. However, the cecum and ileum could be compartmentalized adequately, even by the low and intermittent pressures we recorded. Given that the cecum and ileum are within a common chamber of pressure, the peritoneal cavity, a small pressure differential might suffice to separate cecal flora from the relative sterility of the small bowel. Moreover, the potential of propagated contractions to empty the terminal ileum offers a mechanism for effectively clearing the ileum of reflux. Finally, we are confident that the major features of our findings are not the result of artifacts introduced by intraluminal sensors. We have recorded identical patterns in the dog, using intraluminal sensors in some animals but extraluminal strain gauges and serosal electrodes only in others (12,30). Thus, we feel that motility patterns from the terminal ileum, across the ICS, and from the cecum can be recorded reproducibly in healthy humans. The region’s motility demonstrates sufficient functional specialization to warrant further exploration. References 1. Krag E, Phillips
SF. Active and passive bile acid absorption in man: perfusion studies of the ileum and jejunum. 1Clin Invest 1974:53:1686-94.
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RM Jr, Mackenzie IL. Trier JS. Intrinsic factor2. Donaldson mediated attachment of vitamin Br3 to brush border and microvillus membranes of hamster intestine. J Clin Invest 1967;46:1211-5. 3. Gorbach SL, Plant AG. Nahas L, Weinstein L. Spanknebel G. Levitan R. Studies of intestinal microflora. II. Microorganisms of the small intestine and their relationship to oral and fecal flora. Gastroenterology 1967:53:856-67. 4. Donaldson RM. Toskes PP. The relation of enteric bacterial population to gastrointestinal function and disease. In: Sleisenger MH, Fordtran JS. eds. Gastrointestinal disease. Philadelphia: WB Saunders, 1983:544-54. 5. Kelley ML Jr, DeWeese JA. Effects of eating and intraluminal filling on ileocolonic functional zone pressure. Am J Physiol 1969:216:1491-5. 6. Cohen S, Harris LD. Levitan R. Manometric characteristics of the human ileocecal functional zone. Gastroenterology 1968;54:72-5. JL, Christensen J. Local specialization at ileocecal 7. Conklin junction of the cat and opossum. Am J Physiol 1975: 228:1075-81. J, Snape WJ Jr, Cohen S. Adrenergic a. Rubin MR, Fournet regulation of ileocecal sphincter function in the cat. Gastroenterology 1980;78:15-21. 9. Owyang A, Clain CJ, Snape WJ Jr. Cohen S. Characterization of opiate-mediated responses of the feline ileum and ileocecal sphincter. J Clin Invest 1982;69:507-15. of the colon to electro10. Phillips SF, Giller J. The contribution lyte and water conservation in man. J Lab Clin Med 1973;81:733-46. JC, Phillips SF. Capacity of the human colon to 11. Debongnie absorb fluid. Gastroenterology 1978:74:698-703. EMM. Phillips SF, Dent J. Taylor BM. Myoelectric 12. Quigley activity and intraluminal pressure at the canine ileocolonic sphincter. Gastroenterology 1983;85:1054-62. SF. Interdigestive patterns of intralu13. Quigley EMM. Phillips minal pressure at the canine ileocolonic junction (abstr). Gastroenterology. 1983;84:1279. F, Phillips SF. High pressure propulsive 14. Kruis W. Azpiroz forces of the canine ileum. Clin Ros 1983;31:764A. W. The Huxtley lecture on the function of the 15. Macewen cecum and appendix. Lancet 1904:ii:995-1000. B. Harris AS. Observations 16. White HL, Rainey WR. Monaghan on nervous control of ileocaecal sphincter and on intestinal movements in unanaesthetised human subjects. Am J Physiol 1934:108:449-57. of motility of the ileum and 17. Kerlin P, Phillips SF. Variability jejunum in healthy man. Gastroenterology 1982;82:694-700. A, Phillips SF. Relationship of motility 18. Kerlin P. Zinsmeister to flow of contents in the human small intestine. Gastroenterology 1982;82:701-6. A, Phillips SF. Motor responses to food 19. Kerlin P, Zinsmeister of the ileum, proximal colon, and distal colon of healthy humans. Gastroenterology 1983;84:762-70. SF. Differential transit of liquids and solid 20. Kerlin P, Phillips residue through the human ileum. Am J Physiol 1983:8:G3843. SF, Wienbeck M, Tucker RL. Fasting 21 Quigley EMM. Phillips patterns of motility at the ileocolonic junction in normal man (abstr). Gastroenterology 1983;84: 1279. EMM, Phillips SF, Weinbeck M, Haddad AC. The 22. Quigley effect of morphine on motility, flow and transit in the human ileocolonic junctional region labstr). Gastro Clin Biol 1983:7:727. SF. Rapid intubation of the ileo23. Kerlin P. Tucker R, Phillips colonic region of man. Aust NZ J Med 1983;13:591. RC, Stef JJ. Dodds WJ. Linehan JH. Hogan WJ. 24. Arndorfer
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